KR920003064B1 - Process for preparing hetero cyclic compounds - Google Patents

Abstract

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Description

Method for preparing heterocyclic compound

The present invention relates to heterocyclic compounds, methods for their preparation and pharmaceutical compositions containing the compounds. In particular, the present invention relates to compounds that act on specific 5-hydroxytryptamine (5HT) receptors.

5HT, which is sufficiently endogenous in peripheral nerves and platelets, is known to cause pain in humans through specific action at the 5HT receptor located at the end of primary afferent nerves. Compounds that antagonize the neurological effects of 5HT are known to have analgesic effects such as, for example, alleviation of migraine headaches. 5HT also leads to depolarization of rat vagus nerve tissue specimens isolated through the same 5HT-receptor mechanism, and correlates with inhibition of depolarization and in vivo analgesia.

5HT is also present extensively in the neuronal pathways of the central nervous system, and disorders of this 5HT containing pathway are known to cause changes in behavioral syndromes such as emotional, psychomotor activity, desire and memory abnormalities. Since the same type of neuronal 5HT-receptor is present in the central nervous system as is present in the primary afferent nerve endings, compounds that antagonize the neuronal action of 5HT are schizophrenia, anxiety, obesity and mania. It is useful for treating diseases.

There are a number of vulnerabilities in the methods currently used to treat such diseases. That is, existing migraine treatment methods are non-selective and are administered by the administration of blood and contractors, such as ergotamine, which constrict the blood vessels throughout the body. However, ergotamine causes undesirable and potentially dangerous side effects. Migraine headaches have also been treated in combination with analgesics such as aspirin or paracetamol with analgesics such as methaclopramide, which is extremely limited in value.

Current treatments for mental illnesses such as schizophrenia are accompanied by a number of severe side effects, such as extrapyramidal side effects.

Therefore, there has been a need for a safe and effective drug for treating diseases associated with disorders of the 5HT-containing pathways such as migraine or mental illness such as schizophrenia.

Effective and selective antagonist compounds for neuronal 5HT receptors will play this role.

The inventors have discovered compounds of the 3-imidazolylmethyltetrahydrocarbazolone group which are effective and selective antagonists for the “neuronal” 5HT receptor.

The present invention provides tetrahydrocarbazolone compounds of formula (I), physiologically acceptable salts and solvent compounds thereof, such as hydrates:

Wherein R ¹ is a hydrogen atom or a C _1-10 alkyl, C _3-7 cycloalkyl, C _3-6 alkenyl, phenyl or phenyl-C _1-3 -alkyl group, and R ² , R ³ and R ⁴ One of the groups shown is a hydrogen atom or a C _1-6 alkyl, C _3-7 cycloalkyl, C _2-6 alkenyl or phenyl-C _1-3 alkyl group (either identical or different), each of which is The same as or different from each other, a hydrogen atom or a C _1-6 alkyl group.

It will be appreciated that when R ¹ is a C _3-6 alkenyl group, the double bond may not be adjacent to the nitrogen atom.

In general formula (I), the alkyl groups represented by R ¹ , R ² , R ³ and R ⁴ are linear or branched alkyl groups, for example, methyl, ethyl, propyl, prop-2-yl, butyl, butot -2-yl, 2-methyl prop-2-yl, pentyl, pent-3-yl or hexyl group.

Alkenyl groups can be, for example, propenyl groups.

The phenyl-C _1-3 alkyl group can be, for example, benzyl, phenethyl or 3-phenylpropyl group.

The cycloalkyl group can be, for example, a cyclopentyl, cyclohexyl or cycloheptyl group.

It will be appreciated that the 3-position carbon atom of the tetrahydrocarbazolone ring is asymmetric and may exist in the R or S-structure. The present invention encompasses all of the mixtures, including isomers and racemic mixtures of each of the compounds of Formula (I).

Physiologically acceptable salts of indole of general formula (I) include acid addition salts formed from organic or inorganic acids, such as hydrochloride, hydrobromide, sulfate, phosphate, citrate, fumarate and maleate. The solvent compound may be, for example, a hydrate.

Preferred of the compound represented by the formula (I) is that R ¹ is a hydrogen atom or a C _1-6 alkyl, C _3-6 cycloalkyl or C _3-6 alkenyl group.

Another preferred of the compounds of formula (I) is that one of the groups represented by R ² , R ³ and R ⁴ is a C _1-3 alkyl, C _3-6 cycloalkyl or C _3-6 alkenyl group, each of the other two groups. Are the same as or different from each other, and are hydrogen atoms or C _1-3 alkyl groups.

Other preferred compounds represented by formula (I) include R ¹ being a hydrogen atom or a C _1-6 alkyl, C _5-6 cycloalkyl or C _3-6 alkenyl group, R ² is a hydrogen atom, R ³ and ( Or) R ⁴ is a C _1-3 alkyl group or R ² is a C _1-3 alkyl group and both R ³ and R ⁴ are hydrogen atoms.

Particularly preferred compounds according to the invention are the following general formulas (Ia) and the physiologically acceptable salts and solvent compounds (eg hydrates) of these compounds.

Wherein R ^1a is a hydrogen atom or methyl, ethyl, propyl, prop-2-yl, prop-2-enyl or cyclopentyl group, R ^3a is a hydrogen atom, R ^2a is methyl, ethyl, propyl or Is a prop-2-yl group and R ^4a is a hydrogen atom, or R ^2a is a hydrogen atom and R ^4a is a methyl or ethyl group.

Preferred compounds are as follows.

1,2,3,9-tetrahydro-3-[(2-methyl-1H-imidazol-1-yl) methyl] -9- (prop-2-enyl) -4H-carbazol-4-one ; 9-cyclopentyl-1,2,3,9-tetrahydro-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one; And 1,2,3,9-tetrahydro-3-[(2-methyl-1H-imidazol-1-yl) methyl] -9- (prop-2-yl) -4H-carbazole-4- Warm and physiologically acceptable salts and solvent compounds of said compounds.

Particularly preferred compounds are 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbohydrate represented by the following general formula (Ib) Bazol-4-one and its physiologically acceptable salts and solvates (eg hydrates) are:

Preferred forms of the compound are hydrochloride and dihydrate.

The invention also extends to other physiologically acceptable equivalents, ie physiologically acceptable compounds which are converted in vivo to the parent compound of formula (I).

Compounds of the present invention are effective and selective antagonists for 5HT-induced responses in isolated rat vagus nerve tissue specimens, and therefore are effective and selective antagonists for the neuronal 5HT receptor type located in primary afferent nerves.

The compounds of the present invention are used as painkillers to alleviate migraines, headaches and various other types of pain caused by 5HT as an endogenous mediator.

Animal experiments have demonstrated that the compounds of the present invention can also be used to treat schizophrenia and other psychosis. As described above, 5HT is widely present in the nervous system of the central nervous system, and the disruption of the 5HT-containing pathway is known to cause a change in many behavioral syndromes such as emotions, desires and memory abnormalities. Since the same type of neuronal 5HT receptor is present in the central nervous system as is present in the coincident afferent nerves, the compounds of the present invention will also be useful in treating diseases such as anxiety, obesity and manic.

In particular, the compounds of the general formula (Ia) described above have been shown to be extremely selective and remarkable in their function. This compound is absorbed in the gastrointestinal tract and is suitable for oral or rectal administration. Compounds of formula (Ia) do not prolong sleep time in pentobarbitone anesthetized rats, meaning that they do not have unwanted interaction with drug metabolizing enzymes. In fact, the compound has no effect on normal behavior, is nontoxic, and no adverse effects occur even when intravenously administered 1 mg / kg to mice.

While exhibiting the remarkable properties of the compounds of formula (Ia), there are no side effects of compounds of formula (Ib) upon human administration.

On the other hand, the present invention also provides a treatment for a patient or animal suffering from a disease caused by a disorder of the murine neuron 5HT action. That is, for example, the present invention provides a treatment for psychotic patients such as migraine pain patients or schizophrenia.

Accordingly, the present invention provides at least one 3-imidazolylmethyltetrahydrocarbazolone derivative of formula (I), suitable for use as a human or veterinary agent, and formulated for administration, a physiologically acceptable salt thereof, and Also provided are pharmaceutical compositions composed of compounds selected from solvates (eg hydrates) and the like.

Such compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers or excipients.

That is, the compounds of the present invention may be formulated in a form suitable for oral, oral, parenteral or rectal administration or for administration (through the mouth or nose) by inhalation or aeration.

For oral administration, the pharmaceutical composition may contain a binder (e.g. pregelatinized corn starch, polyvinylpyrrolidone or hydroxy propyl methylcellulose), a filler (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate), a lubricant (e.g. Formulated in a conventional manner with pharmaceutically acceptable excipients such as magnesium stearyl acid, talc or silica), dispersants (eg potato starch or sodium glycolate starch) or wetting agents (eg sodium lauryl sulfate), for example It may be in tablet or capsule form.

Tablets may be coated by conventional methods. Oral administration solution formulations may, for example, be in the form of liquids, syrups or suspensions, or they may be provided as a dry matter which may be recombined with water or other suitable media before use. Such liquid preparations include suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible oils), emulsions (e.g. lecithin or acacia), non-aqueous carriers (e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils), And pharmaceutically acceptable additives such as preservatives (eg, methyl or propyl-p-hydroxybenzoate or sorbic acid).

The formulations may contain buffer salts, perfumes, pigments and sweeteners as necessary.

Formulations for oral administration may be suitably formulated for controlled release of the active compound.

Formulations for oral administration may be in the form of tablets or dragees formulated in conventional manner.

The compounds of the present invention can be shaped for parenteral administration by injection. Injectable preparations may be present with the added preservative in, for example, unit dosage forms in ampoules or in multidose containers. The compositions may be in the form of suspensions, solutions or emulsions, for example in oils or water soluble excipients, and may not contain formulating agents such as suspensions, stabilizers and / or dispersants. Alternatively the active ingredient may be in the form of a powder for reconstitution with a suitable excipient, eg, pyrogen-free sterile water, before use.

The compounds of the present invention may also be formulated in rectal compositions such as suppositories or retention enemas (eg, containing conventional suppository bases such as butter or other glycerides).

In addition to the above compositions, the compounds of the present invention may also be formulated as a depot preparation. Such long-acting agents can be implanted, for example, subcutaneously or intramuscularly or by intramuscular injection. That is, for example, the compounds of the present invention may be formulated as suitable polymers or hydrophobic materials (eg emulsions in acceptable oils) or ion exchange resins, or poorly soluble derivatives (eg poorly soluble salts).

For inhalation administration, the compounds of the present invention can be packaged to enhance the atmospheric pressure using a suitable tetramer, for example dichlorodifluoromethane, trichloro fluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. Or in the form of an aerosol spray in a nebulizer. In the case of an aerosol with enhanced air pressure, the dosage unit may be determined by providing a valve for deriving the metric amount. Capsules or cartridges, for example gelatin, to be used in an inhaler or aeration inhaler may be formulated to contain a powder mixture of a compound of the invention and a suitable powder such as lactose or starch.

The dose of the compound of the present invention (about 70 kg body weight) administered to the human body is 0.05-20 mg, preferably 0.1-10 mg of the active ingredient per unit dose when administered 1-4 times daily. The exact dosage depends on the age and weight of the patient. Of course, there is a need to adjust the dosage routinely according to the age and weight of the patient and the symptoms of the disease.

In oral administration, the unit dose preferably contains 0.5-10 mg of the active ingredient. The unit dosage for non-oral administration preferably contains 0.1-10 mg of the active ingredient.

The aerosol formulations may be administered in a gas pressure aerosol, or each dose administered via a capsule or cartridge in an air inhaler or inhaler containing a meter or puff of the compound of the present invention, or 0.2-2 mg of the present invention. It is appropriately adjusted to contain 0.2-20 mg of the compound. The total daily dose by inhalation is 0.4-80 mg. Administration can be, for example, 2 to 8, several times a day, for example with a dose of 1, 2 or 3 each time.

The compounds of the present invention may be administered in combination with one or more therapeutic agents, such as antiemetic agents, as desired.

According to the invention, the compounds of general formula (I) and pharmacologically acceptable salts or solvent compounds or pharmacologically acceptable equivalents thereof can be prepared by the following general methods.

According to the first general process (A), the compound of formula (I) or a pharmacologically acceptable salt or solvate thereof or a pharmacologically acceptable equivalent thereof may be prepared by combining a compound of formula (II) or a protected derivative thereof It can be prepared by reacting with an imidazole of formula (III) or a salt thereof:

Wherein R ¹ , R ² , R ³ and R ⁴ are as defined above and Y is a reactive substituent.

기(X는 염화물, 취소화물 또는 요오드화물과 같은 할로겐화 음이온임)기이거나, 또는 R⁵와 R⁶가 상기한 바와 같은 -NR⁵R⁶(예 : -N(CH₃)₂인 CH₂Z기를 나타내는 화합물이다.Examples of compounds of formula (II) used as starting materials in process (A) are those in which Y is an alkenyl group (= CH ₂ ) or Z is an easily substituted atom or group as a halogen atom (e.g. chlorine or Acyloxy groups such as acetoxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy or methanesulfonyloxy, and R ⁵ , R ⁶ and R ⁷ may be the same or different and each may be a lower alkyl (e.g., : Methyl), aryl (e.g. phenyl) or aralkyl (e.g. benzyl or a 5-6 membered ring (e.g. pyrrolidine ring) with the nitrogen atom to which R ⁵ and R ⁶ are linked thereto

A group (X is a halogenated anion such as chloride, cancelide or iodide) or CH ₂ Z in which R ⁵ and R ⁶ are -NR ⁵ R ⁶ as described above (eg -N (CH ₃ ) ₂ ) It is a compound which shows a group.

When Y is = CH ₂ , the process is a suitable solvent such as water, esters (e.g. ethyl acetate), ketones (e.g. acetone or methyl isobutyl ketone), amides (e.g. dimethylformamide). , Alcohols (eg ethanol) and esters (eg dioxane or tetrahydrofuran) or a mixture of the above solvents. This process can be carried out, for example, at a temperature of 20-100 ° C.

If Y is CH ₂ Z, wherein Z is a halogen atom or an acyloxy group, then the process may be an amide (e.g. dimethyl formamide), an alcohol (e.g. methanol or industrial methylated spirit) or a haloalkane (e.g. dichloromethane). It can be conveniently carried out at a temperature of -10 ℃ -150 ℃ (for example + 20-100 ℃) in a solvent such as.

를 나타내는 일반식(II)의 화합물의 반응은 물, 아미드(예 : 디메틸포름 아미드), 케톤(예 : 아세톤), 에테르(예 : 디옥산)과 같은 적당한 용매중에서 20-150℃의 온도에서 편리하게 진행시킬 수 있다.Y is CH ₂ Z, where Z is

The reaction of a compound of formula (II) is convenient at a temperature of 20-150 ° C. in a suitable solvent such as water, amide (e.g. dimethylformamide), ketone (e.g. acetone), ether (e.g. dioxane). You can proceed.

The reaction of the compound of formula (II) wherein Y is -CH ₂ Z, wherein Z represents -NR ⁵ R ⁶ is carried out at 20-150 ° C. in a suitable solvent such as water or alcohol (eg methanol), or mixtures thereof. It can be done conveniently at temperature.

According to another general process (B), the compound of general formula (I) can be prepared by oxidizing the compound of general formula (IV) or a salt or protected derivative thereof:

(Wherein A is a hydrogen atom or a hydroxyl group, and R ¹ , R ² , R ³ and R ⁴ are as defined above)

The oxidation reaction is carried out according to a conventional method by selecting reagents and reaction conditions that do not cause oxidation of indole groups. That is, the oxidation reaction is preferably performed using a gentle oxidant.

Suitable oxidizing agents when oxidizing a compound of formula (IV) wherein A is a hydrogen atom are quinones (e.g., 2,3-dichloro-5,6-dicyano-1,4-benzoquinone or 2,3) in the presence of water. Cerium (IV) oxidant such as 5,6-tetrachloro-1,4-benzoquinone), selenium dioxide, cesium ammonium nitrate or a solution of chromic acid in acetone (eg Jones reagent) or chromium trioxide in pyridine And chromium (VI) oxidants.

Suitable oxidizing agents when oxidizing a compound of formula (IV) wherein A is a hydroxyl group are quinones (e.g., 2,3-dichloro-5,6-dicyano-1,4-benzoquinone or 2, 3,5,6-tetrachloro-1,4-benzoquinone), ketones in the presence of a base such as aluminum t-butoxide (e.g. acetone, methylethylketone or cyclohexanone), a solution of chromic acid in acetone (e.g. Jones Reagents) or chromium (VI) oxidants such as chromium trioxide solution in pyridine, N-halosuccinimide (e.g., N-chlorosuccinimide or N-bromosuccinimide), N, N'-dicyclohexylcarba Dialkyl sulfoxides (e.g. dimethyl sulfoxide), pyridine-sulfur trioxide complexes or copper chromite, zinc oxide, copper or silver in the presence of an activating reagent such as a bodyimide or an acyl halide (e.g. oxalyl chloride or tosyl chloride) It is the same dehydrogenation catalyst.

Suitable solvents include ketones (e.g. acetone or butanone), ethers (e.g. tetrahydrofuran or dioxane), amides (e.g. dimethylformamide), alcohols (e.g. methanol), hydrocarbons (e.g. benzene Or toluene), halogenated hydrocarbons (eg dichloromethane) and water, or mixtures thereof.

The process is conveniently carried out at -70 ° C to + 50 ° C. It will be appreciated that the choice of oxidant affects the desired reaction temperature.

By another general step (C), the compounds of the general formula (I) or salts or derivatives thereof according to the invention can be converted to other compounds of the general formula (I) by conventional methods. Such conventional methods can be used to convert alkyl and alkylene substituents, for example, to alkyl substituents, which can be achieved at any position in the compound of formula (I) in which one or more of R ¹ and R ² represent a hydrogen atom. Hydrogenation and the like. "Alkylated" refers to the introduction of other groups, such as cycloalkyl or alkenyl groups. That is, for example, a compound of formula (I) wherein R ¹ is a hydrogen atom may have a corresponding R ¹ of C _1-10 alkyl, C _3-7 cycloalkyl, C _3-6 alkenyl or phenyl-C ₁ It can be converted into a compound which is a _-3 alkyl group.

The alkylation reaction is such that R ^a is C _1-10 alkyl, C _3-7 cycloalkyl, C ₃ -C ₆ alkenyl or phenyl-C _1-3 alkyl group, X ^a is ^a leaving group such as ^a halide or in Z It may be carried out using an acyloxy group as defined, or ^a suitable alkylating agent selected from compounds of the formula R ^a X ^{a which} are sulfates of (R ^a ) ₂ SO ₄ .

The alkylation reaction is carried out in an inert organic solvent such as amide (eg dimethylformamide), ether (eg tetrahydrofuran) or aromatic hydrocarbon (eg toluene), preferably in the presence of a base. Suitable bases are, for example, alkali metal hydrides such as sodium hydride, alkali metal amides such as sodium amide, alkali metal carbonates such as sodium carbonate or alkali metal alkoxides such as sodium or potassium methoxide, ethoxide or t-butoxide to be. The reaction may conveniently be carried out at a temperature of −20 ° C. to + 100 ° C., preferably at a temperature of 0-50 ° C.

Hydrogenation according to the general process (C) can be carried out using hydrogen, for example, in the presence of a conventional metal catalyst (eg palladium, raney nickel, platinum, platinum oxide or rhodium). The catalyst can be, for example, a catalyst described on charcoal or a homogeneous catalyst such as tris (trimethylphosphine) rhodium chloride. The hydrogenation reaction is carried out at a temperature of -20 ° C to 100 ° C, preferably in a solvent such as alcohol (e.g. ethanol), amide (e.g. dimethylformamide), ether (e.g. dioxane) or ester (e.g. ethyl acetate). It may be carried out at a temperature of 0-50 ℃.

It is necessary and desirable to protect any group sensitive to the reaction present in the compound in order to prevent side reactions during the conversion reaction. The protecting group used in the preparation of the compound of formula (I) is suitably a group which can be easily released at a suitable stage during the reaction, conveniently at the last stage. For example, it may be necessary at some stage of the reaction process to protect the keto group, for example as a ketal or thioketal group.

Compounds of formula (I) may be prepared by another general process (D) which removes a protecting group from a compound of formula (I) in protected form. Deprotection is described in ＂Protective Groups in Organic Chemistry＂ Ed. It may be performed by conventional methods such as those described in J. F. W. McOmie (Plenium Publishing, 1973). That is, ketals, such as alkylene ketal groups, are removed by treatment with formic acid, such as hydrochloric acid. Thioketal groups are removed by treatment with a second mercury salt (e.g., a second mercuric chloride salt) in a suitable solvent such as ethanol.

Compounds of formula (I) may be converted to physiologically acceptable salts by conventional methods. That is, for example, the free base of general formula (I) can be treated in the same amount in a suitable acid, preferably in a suitable solvent (such as an aqueous ethanol solution).

The physiologically acceptable equivalent compound of general formula (I) can be manufactured by a conventional method.

Each enantiomer of the compound of the invention can be obtained by dividing an enantiomer mixture, for example a racemic mixture, using conventional methods, such as an optically active splitting acid [eg, EL Eliel (McGraw Hill). Stereochemistry of carbon compounds according to 1962) and "Table of the splitting reagents by SH Wilen".

Examples of optically active cleavable acids that can be used to form salts with racemic compounds include (R) and (S) of organic carboxylic and sulfonic acids such as tartaric acid, di-p-toluoyltartaric acid, camphorsulfonic acid and lactic acid. Type is included. The mixture of isomer salts thus produced can be separated into diastereoisomers by, for example, fractional crystallization, and the active isomers can be converted into the free base as needed.

The above described method for preparing the compounds of the present invention can be used as the last major step in the preparation sequence. It will be appreciated that the same general method may be used to introduce the desired groups in the intermediate step in the stepwise formation of the desired compound, and that this general method may be combined in different ways in this multistep process. Of course, in this multi-step process the order of reactions can be chosen such that the reaction conditions used do not affect the groups in the molecule required in the final product.

인 일반식(II)의 화합물을 적합한 용매중에서 염기와 반응시켜 제조할 수 있다. 염기의 예는 알칼리 금속 수산화물류(예 : 수산화 칼륨) 또는 알칼리 금속 탄산염 또는 탄산수소 알카리금속(예 : 탄산수소나트륨)등이다.Starting materials of the general formula (II) wherein Y is = CH _2, Y is CH ₂

The compound of formula (II) may be prepared by reacting with a base in a suitable solvent. Examples of bases are alkali metal hydroxides (such as potassium hydroxide) or alkali metal carbonates or alkali hydrogen carbonate metals (such as sodium hydrogen carbonate).

Quaternary salts may be prepared by reacting the corresponding tertiary amine with an alkylating agent such as methyl iodide or dimethyl sulfate in a suitable solvent, such as dimethylformamide, as desired. Tertiary amines may be prepared by reacting tetrahydrocarbazolone of general formula (V) with formaldehyde and the corresponding secondary amine in a suitable solvent such as alcohol (e.g. ethanol) as needed:

Compounds of formula (V) are, for example, H, Iida et al., J, Org. Chem, (1980) 45, No. 15, p.2938-2942.

Starting materials of formula (II), wherein Y represents -CH ₂ Z, wherein Z is a halogen atom or an acyloxy group, can be prepared from hydroxymethyl derivatives of which formula (VI) corresponds to this intermediate ( VI) can be obtained by reacting tetrahydrocarbazolone of formula (V) with formaldehyde, preferably in the presence of a base, in a suitable solvent such as an alcohol (eg ethanol).

That is, a compound in which Z is a halogen atom can be prepared by reacting a compound of formula (VI) with a halogenating reagent such as phosphorus trihalide (eg, trichloride salt).

Compounds in which Z is an acyloxy group can be prepared by reacting a compound of formula (VI) with a suitable acylating agent, for example anhydride or a halogenated sulfonyl such as sulfonyl chloride.

Compounds of formula (II) wherein Y represents -CH ₂ Z, wherein Z is a halogen atom, are useful in formulating compounds of formula (II) wherein Y is = CH ₂ , with a suitable hydrogen halide such as hydrogen chloride. It may also be prepared by reaction in a suitable solvent such as ether (e.g. diethyl ether).

Compounds of formula (IV) may be prepared by reacting compounds of formula (VII) with imidazoles of formula (III) according to the process (A) described above:

기임.)Wherein R ¹ and A are as defined above and Z ¹ is an easily released atom or group such as a halogen atom, an acyloxy group or as defined above in Z

Appointed.)

The compound of formula (VII) can be prepared by reducing the compound of formula (II) using, for example, lithium aluminum hydride or sodium borohydride.

The compound of formula (VII) in which A is a hydrogen atom reacts the compound of formula (VII) in which A is a hydroxyl group with tosyl halide (e.g., tosyl chloride), and the resulting tosylate is converted into lithium aluminum hydride. It may also be prepared by reduction.

The compound wool of general formula (IV) is a novel compound, which itself constitutes another feature of the present invention.

The following examples illustrate the invention. The temperature is ° C.

In the example the solution was dried over Na ₂ SO ₄ and the solid was vacuum dried over P ₂ O ₅ at 50 ° C. overnight. Chromatography was performed on KieseIgel 9385 using the method described by WCStill et al. (J. Org. Chem., 1978, 43, 2923-2925).

[Production Example 1]

2,3,4,9-tetrahydro-N, N, N-trimethyl-4-oxo-1H-carbazole-3-methane aluminum iodine salt

3-[(dimethylamino) methyl] -1,2,3,9-tetrahydro-4H-carbazol-4-one (0.53 g) solution in iodine methane (15 ml) was heated to reflux for 5 hours and then evaporated to dryness. To give the title compound (0.84 g) as a white solid.

Melting point 202-205 ° C.

[Production Example 2]

2,3,4,9-tetrahydro-N, N, N, 9-tetramethyl-4-oxo-1H-carbazole-3-methane aluminum iodine salt

3-[(dimethylamino) methyl] -1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one (3.80 g) suspension in iodine methane (100 ml) was stirred at reflux for 57 hours. . The suspension was then concentrated in vacuo to give the title solid methaneamido iodide (5.72 g). Melting Point192 ℃ -195 ℃

[Manufacture example 3]

1,2,3,9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one

The solution of the product of Preparation Example 2 (5.0 g) in water (20 ml) was treated with 2N sodium carbonate (6.55 ml) and then warmed at 35 ° C. for 45 minutes. The resulting slurry was cooled to 0 ° C., and then the solid was filtered, washed with water and dried to give the title compound (2.8 g). Melting point 127-9 ° C.

[Production Example 4]

2,3,4,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -1H-carbazole maleate

Sodium borohydride (90 mg) was added to a stirred solution of the product of Example 7 (500 mg) in a mixture of methanol (3 ml) and chloroform (3 ml) under a nitrogen atmosphere. After continuing stirring for 48 hours (addition of sodium borohydride (250 mg) after 17.75 hours and 42 hours), the suspension was partitioned into 2N hydrochloric acid (15 ml) and chloroform (3 × 10 ml). The aqueous layer was basified with solid sodium carbonate, extracted with chloroform (3 × 10 ml), the extract mixture was washed with water (2 × 10 ml) and brine (10 ml), dried and concentrated in vacuo. The residue foam (557 mg) was eluted with a mixture of dichloromethane, ethanol and 0.88 ammonia water (300: 10: 1) to give a solid (200 mg). This material was dissolved in reflux anhydrous ethanol (3 ml), and then maleic acid (80 mg) solution in 1 ml of reflux anhydrous ethanol was added thereto. The solution was stirred in hot state and diluted with anhydrous ether (40 ml) to afford the title compound (240 mg). Melting point 138.5 ° C-140 ° C.

Production Example 5

2,3,4,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -1H-carbazol-4-one

The product of Example 7 (30.0 g) was added to a stirred suspension of lithium aluminum hydride (7.75 g) in anhydrous tetrahydrofuran (750 ml) under a nitrogen atmosphere. The mixture was stirred at reflux for 1 hour and then ice-cooled. The suspension was carefully diluted with aqueous tetrahydrofuran solution (15% H ₂ O; 100 ml) and water (200 ml), then concentrated in vacuo, and the solid residue was extracted with dichloromethane (2 × 500 ml). The organic extracts were concentrated in vacuo, using short residue column chromatography on silica (Kieselgel 60; Merck 7747; 500 g) using a solid residue (16.4 g) as a eluent mixture of dichloromethane, ethanol and 0.88 aqueous ammonia (150: 10: 1). ) To give a foamy title compound (13.4 g). Thin layer chromatography (T.1.C) silica, dichloromethane / ethanol / 0.88 ammonia (150: 10: 1) Rf 0.34 and 0.36 (two pairs of diastereoisomers), ultraviolet detection and iodic full acid.

NMR δ [CDCl ₃ + CD ₃ OD (1 drop)] 1.6-2.3 and 2.6-3.0 (5H, m), 2.32 and 2.40 (3H, s + s, Me of two other isomers), 3.32 (3H, s , NMe), 3.65-4.3 (2H, m, CHCH ₂ N), 4.75-4.85 (1H, m, CH-OH), 6.8-7.8 (CH, m, aromatic).

Example 1a

1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one hydrochloride

The solution of 2-methylimidazole (5.0 g) and the product of Preparation Example 2 (2.0 g) in anhydrous dimethylformamide (30 ml) were stirred at 95 DEG C for 16.75 hours under a nitrogen atmosphere, and then cooled. The solid produced by crystallization was filtered and washed with anhydrous dimethylformamid (3 × 2 ml) and anhydrous ether (2 × 10 ml) at ice water temperature to obtain a solid. The resulting solid (0.60 g) was suspended in a mixture of anhydrous ethanol (30 ml) and ethanol hydrogen chloride (1 ml), warmed to a solution, and filtered while warming. The filtrate was diluted with anhydrous ether and the precipitated solid (0.6 g) was recrystallized from anhydrous ethanol to give the title compound as a solid (0.27 g). Melting point 186-187 ° C.

Elemental Analysis for C ₁₈ H ₁₉ N ₃ O · HCl · H ₂ O

Found (%): C; 61.9, H; 6.4, N; 11.8

Theoretical value (%): C; 62.3, H; 6.1, N; 12.1

The following compounds were prepared by analogous processes as described in Table 1.

TABLE 1

2,3,4,9-Tetrahydro-9, N, N, N-tetramethyl-p-oxo-1H-carbazole-3-methanealuminum methosulfate was used as starting material.

In the table, II is Indicates.

[Note 1]

Compounds Ie and If were prepared in the same experiment, and isomers were used as eluents with dichloromethane / ethanol / 0.88 ammonia (300: 10: 1) for short-path chromatography (DF Taber, J. Org. Chem., 1982, 47). , 1351). The following ¹ H-NMR data was obtained.

1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one maleate

1,2,3,9-tetrahydro-9-methyl-3-[(2-methylimidazol-1-yl) methyl] -4H-carbazol-4-one (300 mg) in hot ethanol (5 ml) After being suspended in, it was treated with maleic acid (116 mg). The resulting solution was cooled and the resulting white crystalline solid was filtered and dried to afford the title compound (300 mg). Melting point 132-3 ° C.

Example 3a

1,2,3,9-tetrahydro-3- (1H-imidazol-1-yl-methyl) -4H-carbazol-4-one

A solution of imidazole (0.90 g) and product of Preparation Example 1 (0.84 g) in dimethylformamide (25 ml) was heated at 105 ° C. for 6 hours, cooled, and then water (200 ml) was added thereto, followed by ethyl acetate. Extracted six times. The extract mixture was washed, dried and evaporated to give a solid product which was purified on a silica column (Merck 7734) using ethyl acetate / methanol (4: 1) as eluent. It was recrystallized twice with ethyl acetate / methanol (4: 1) to afford the title compound (0.095 g) as a solid. Melting point 220-222 ° C. Thin layer chromatography, silica, dichloromethane / ethanol / 0.88 ammonia (100: 8: 1) Rf 0.33, ultraviolet detection and iodineplatinic acid.

The following compounds were prepared by analogous processes as in Table 2. The method of forming the salt was done as described in Example 2.

TABLE 2

[Note 1]

Compounds 3e and 3f were prepared in the same experiment, and isomers were separated by preparative HPLC on Zorbax-Sil with hexane / ethyl acetate / ethanol / 0.88 ammonia (400 = 100: 100: 0.6) as eluent.

를 나타낸다.In the table, γ is

Indicates.

Example 4

1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one

1,2,3,9-tetrahydro-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one (1.0 g) in anhydrous dimethylformamide (10 ml) ) Solution was added dropwise to a stirred ice cold suspension of sodium hydride (80% oil phase; 0.11 g) in anhydrous dimethylformamide (5 ml) under a nitrogen atmosphere. After 0.5 hour, dimethyl sulfate (0.34 ml) was added, and the solution was stirred at room temperature for 4 hours. The resulting solid was filtered, washed with anhydrous dimethylformamide (2 × 5 ml) and anhydrous ether (3 × 15 ml) cooled at ice water temperature and dried to afford the title compound (0.25 g) as a solid. Melting point 223-224 ° C. (dec.).

Thin layer chromatography, silica, chloroform / methanol (93: 7) Rf 0.27 UV detection and iodineplatinic acid, same as the product in Example 1a.

The following compounds were prepared by analogous processes using the appropriate alkylating agents as described in Table 3.

TABLE 3

[Note 1]

The following ¹ H NMR data was obtained.

Example 5

9-cyclopentyl-1,2,3,9-tetrahydro-3 [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one maleate

1,2,3,9-tetrahydro-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one (1.20 g) in anhydrous dimethylformamide (9 ml) The solution was added to a water-stirred suspension in which sodium hydride (80% oil phase; 0.14 g) in anhydrous dimethylformamide (2 ml) was cooled to ice water temperature under a nitrogen atmosphere, and the stirring was continued for 0.25 hours. Bromocloclopentane (0.51 ml) was added thereto, and the solution was heated and stirred at 100 ° C. for 18.5 hours. The solution was cooled and partitioned between water (100 ml) and ethyl acetate (3 x 70 ml). The combined organic extracts were washed with 2N sodium carbonate (2 × 50 ml), water (2 × 50 ml) and brine (50 ml), then evaporated to dryness and a mixture of dichloromethane / ethanol / 0.88 ammonia (150: 10: 1) was obtained. The product was purified by chromatography using an eluent to obtain an oil (0.27 g). This oil was dissolved in reflux anhydrous ethanol (7 ml), and maleic acid solution (0.10 g) in reflux anhydrous ethanol (0.5 ml) was added thereto. The hot solution was filtered off, stirred and diluted with anhydrous ether (20 ml). The yellow gum thus produced was washed with anhydrous ether (7 × 25 ml) to leave the mixed mother liquor and wash solution. The solid crystallized from the solution was filtered, washed with anhydrous ether (3 x 5 ml) and dried to afford the title salt as a white crystalline solid (0.058). Melting point 104.5 ° C-106 ° C.

Elemental Analysis for C ₂₂ H ₂₅ N ₃ O · C ₂ H ₄ O ₄ · 0.6H ₂ O

Found (%): C; 65.95, H; 6.4, N; 8.6

Theoretical value (%): C; 65.8, H; 6.4, N; 8.9

Example 6

1,2,3,9-tetrahydro-3-[(2-methyl-1H-imidazol-1-yl) methyl] -9- (2-propenyl) -4H-carbazol-4-one maleate

1,2,3,9-tetrahydro-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one (1.0 g) in anhydrous dimethylformamide (6 ml) ) Solution was added to a stirred suspension cooled to an ice temperature of sodium hydride (80% oil phase; 0.12 g) in anhydrous dimethylformamide (2 ml). After 0.25 hours, allyl bromide was added thereto, and the solution was stirred at 0 ° C. for 0.25 hours and at room temperature for 20 hours, and then partitioned into water (75 ml) and ethyl acetate (3 × 50 ml). The combined organic extracts were washed with water (2 × 50 ml) and brine (50 ml), dried, concentrated in vacuo, and then chromatographed using a dichloromethane / ethanol / 0.88 ammonia water (200: 10: 1) mixture as a solution. Purification by the product gave a solid (0.43 g). This solid was dissolved in reflux anhydrous ethanol (2 ml), and a solution of maleic acid (0.18 g) in reflux anhydrous ethanol (1 ml) was added to this solution. The hot solution was filtered and then diluted with anhydrous ether (4 ml), then the crystallized solid was filtered off, washed and dried with anhydrous ether (3 x 5 ml) to give the title compound as a white solid (0.48 G). Melting point 150.5 ° C-151 ° C.

Elemental Analysis for C ₂₀ H ₂₁ N ₃ O · C ₂ H ₄ O ₅

Found (%): C; 66.3, H; 5.75, N; 9.6

Theoretical value (%): C; 66.2, H; 5.8, N; 9.65

Example 7

1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one

2-methylimida solution of 3-[(dimethylamino) methyl] -1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one hydrochloride (1.7 g) in water (17 ml) After treatment with sol (1.4 g), it was heated to reflux for 20 hours. The cooled mixture was filtered and the residue was washed with water (3 x 15 ml) to give a crude product (1.7 g) with a melting point of 221-221.5 占 폚. This material was recrystallized from methanol to give the title compound (1.4 g) with a melting point of 231-232 ° C., which was confirmed by thin layer chromatography to be the same as the product of Example 4.

Example 8

1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one

A suspension of the product of Preparation 3 (0.5 g) and 2-methyl imidazole (0.4 g) in water (5 ml) was heated to reflux for 20 hours. The cooled reaction mixture was filtered, the residue was washed with water (3 × 10 ml), dried and recrystallized with methanol (18 ml) to give the title compound (0.3 g) having a melting point of 232-234 ° C. (dec.). It was confirmed by TlC that this compound was consistent with the product of Example 4.

Example 9

1,2,3,9-tetrahydro-9- (1-methylethyl) -3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one hydrochloride

Sodium hydride (0.208 g of 80% oil phase dispersion) was added to 1,2,3,9-tetrahydro-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbide in DMF (35 ml). After addition to the stirred solution of bazol-4-one (1.93 g) at 0 ° C., the resulting suspension was stirred at 0 ° C. for 0.25 hours. Then 2-bromopropane (0.78 ml) was added and stirring was continued overnight at room temperature followed by 4 hours at 40 ° C.

The reaction mixture was partitioned between sodium carbonate (2N; 200 ml) and ethyl acetate (2 x 150 ml). The combined organic extracts were washed with water (3 × 75 ml), dried and evaporated in vacuo, and the product was purified by chromatography using dichloromethane: ethanol: ammonia (100: 8: 1) as eluent to afford an oil. This oil was dissolved in ethanol (3 ml), acidified with etheric hydrogen chloride and diluted with anhydrous ether to afford the title compound as a white solid (0.13 g). Melting point 230-232 ° C.

Elemental Analysis for C ₂₀ H ₂₃ N ₃ O · HCl · 0.5H ₂ O

Found (%): C; 65.3, H; 6.6, N; 11.1

Theoretical value (%): C; 65.4, H; 6.9, N; 11.45

Example 10

1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one hydrochloride dihydrate

1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H in a hot mixture of isopropanol (90 ml) and water (18.3 ml) Carbazol-4-one (18.3 g) was treated with concentrated hydrochloric acid (6.25 ml). The mixture was filtered while hot, the filtrate was diluted with isopropanol (90 ml), stirred at room temperature for 17 hours, cooled to 2 ° C, and the resulting solid was filtered off. (21.6g). Sample (6 g) was recrystallized from a mixture of water (6 ml) and isopropanol (10 ml) to afford the title compound as a white crystalline solid (6 g). Melting point 178.5-179.5 ° C.

Elemental Analysis for C ₁₈ H ₁₉ N ₃ O · HCl · 2H ₂ O

Found (%): C; 59.45, H; 6.45, N; 11.5

Theoretical value (%): C; 59.1, H; 6.6, N; 11.5

Moisture analysis for C ₁₈ H ₁₉ N ₃ O · HCl · 2H ₂ O

Found (%): 10.23

Theoretic Value (%): 9.85

Example 11

1,2,3,9-tetrahydro-3-[(2-methyl-1H-imidazol-1-yl) methyl] -9-phenyl-4H-carbazol-4-one maleate

i) 3-[(dimethylamino) methyl] -1,2,3,9-tetrahydro-9-phenyl-4H-carbazol-4-one hydrochloride

A solution of 1,2,3,9-tetrahydro-9-phenyl-4H-carbazol-4-one (3.90 g), dimethylamine hydrochloride (1.50 g) and paraformaldehyde (0.60 g) in glacial acetic acid was nitrogen atmosphere. After stirring under reflux for 42 hours, the mixture was cooled and concentrated in vacuo. The brown residue gum was stirred for 0.25 h with water (50 ml), ethyl acetate (50 ml) and brine (20 ml), the resulting solid was filtered off, washed with anhydrous ether (4 x 30 ml) and dried to give the title compound. (4.2 g) was obtained. A portion of this solid (1.0 g) was recrystallized twice with anhydrous ethanol (10 ml) to give the title compound as pale tan powder (0.39 g). Melting point 193 ° C.-194 ° C. (dec.).

ii) 1,2,3,9-tetrahydro-3-[(2-methyl-1H-imidazol-1-yl) methyl] -9-phenyl-4H-carbazol-4-one maleate

2-methyl-1H-imidazole (1.4 g) was added to 3-[(dimethylamino) methyl] -1,2,3,9-tetrahydro-9-phenyl-4H-carbazole in water (20 ml) under nitrogen atmosphere. To a stirred suspension of 4-one hydrochloride (2.0 g) was added. The mixture was heated at 90 ° C. for 43 hours and then the solvent was poured off from the resulting pale brown solid. Chloroform was added to the solid, and the suspension was filtered through hyflo, and the filtrate was dried and then concentrated in vacuo. A light brown residue bubble (2.04 g) was chromatographed using a mixture of dichloromethane, ethanol and 0.88 aqueous ammonia solution (200: 10: 1) as eluent to give a white bubble (1.1 g). The foam solution in ethanol (3 ml) was treated with maleic acid (0.4 g) in methanol (1 ml) followed by anhydrous ether (40 ml) and the resulting gum was treated with anhydrous ether (2 x 40 ml) to give the title compound. Was obtained as a creamy solid (1.37 g). Melting point 165-166 ° C. (dec.).

Analysis of elements for C ₂₃ H ₂₁ N ₃ O · C ₄ H ₄ O ₄

Found (%): C; 68.65, N; 5.5, N; 8.7

Theoretical value (%): C; 68.8, N; 5.3, N; 8.9

Example 12

1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one phosphate (1: 1)

1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one (0.61 g) 90%, 0.13 ml) and water (10 ml) were dissolved in a hot mixture, filtered through hyflo and crystallized to give the title compound (0.5 g). Melting point 225 ° C.

Elemental Analysis for C ₁₇ H ₁₉ N ₃ O · H ₃ PO ₄

Found: C; 55.1, H; 5.6, N; 10.55

Theoretical: C; 55.2, H; 5.7, N; 10.7%

Example 13

1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one citrate (2: 1)

1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one (0.89 g) was added to ethanol ( 20 ml) was dissolved in a hot solution of citric acid (0.58 g) and left to form crystals. The crystalline solid thus formed was dissolved in acetone / water (2: 1.2 ml) and recrystallized and diluted with acetone (20 ml) to give the title compound (0.6 g). Melting point162 캜.

Example 14

1,2,3,9-tetrahydro-3-[(2-propyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one hydrochloride

Iodomethane (0.75 ml) was added to a stirred solution of 3-[(dimethylamino) methyl] -1,2,3,9-tetrahydro-4H-carbazole-4one (2.9 g) in anhydrous DMF (30 ml). It was added and the solution was stirred at room temperature for 30 minutes. To this was added a solution of 2-propyl-1H-imidazole (2 g) in DMF (5 ml), the solution was stirred at 100 ° C. for 2 days, then cooled, sodium carbonate (2N, 150 ml) and ethyl acetate (2 × 100 ml) Divided into. The mixed extract was washed with water (10 ml), dried and the solvent was evaporated off in vacuo. The residue was purified by column chromatography using dichloromethane: ethanol: ammonia (400: 30: 3) as eluent to obtain the free base as a solid (1.2 g). A sample (2.0 g) was dissolved in anhydrous ethanol (5 ml), acidified with etheric hydrogen chloride and diluted with anhydrous ether (about 200 ml) to give an oil. Scratching to crystallize the oil to give a solid (0.15 g). The salt was crystallized from a mixture of methanol and isopropyl acetate to give the title compound (0.08 g). Melting point 206 캜 -208 캜.

Elemental Analysis for C ₁₉ H ₂₁ N ₃ O · HCl · 0.2H ₂ 0

Found: C; 65.6, H; 6.8, N; 12.0

Theoretical: C; 65.7, H; 6.5, N; 12.1%

NMR δ (CD ₃ SOCD ₃ ): 0.94 (3H, t, CH ₃ ), 1.77 (2H, sext, CH ₂ CH ₂ CH ₃ ), 1.9-2.15 and 2.93-3.2 (7H, m), 4.32 and 4.71 (2H, ABX, CHCH ₂ N), 7.1-8.0 (6H, aromatic)

Example 15

1,2,3,9-tetrahydro-3-[(2-propyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one hydrochloride

A solution of Example 3 g of product (0.03 g) in methanol (15 ml) was hydrogenated at room temperature over 4 hours (H ₂ uptake, 5 ml) on charcoal (50% aqueous ointment, 0.03 g) based on 10% palladium oxide. The catalyst was filtered off and the filtrate was evaporated in vacuo to give an oil. This oil was treated with ether to give the title compound (0.03 g) as a white solid. Melting point 199 ° C-203 ° C.

The material was confirmed to be the same as the product of Example 14 by thin layer chromatography and NMR.

Example 16

1,2,3,9-tetrahydro-9-propyl-3-[(2-propyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one hydrochloride.

Sodium hydride (80% oil dispersion) was added to a stirred solution of the product of Example 14 (1.0 g) in anhydrous DMF (20 ml) under a nitrogen atmosphere and the suspension was stirred at room temperature for 30 minutes. 1-bromopropane (0.35 ml) was added thereto, and the solution was stirred at 40 ° C. for 20 hours. The solution was partitioned between sodium carbonate (2N, 150 ml) and ethyl acetate (2 x 100 ml). The mixed extract was washed with water (100ml), dried and evaporated to give an oil. This oil was purified by column chromatography using dichloromethane: ethanol: ammonia (100: 8: 1) as eluent to obtain pure free base as an oil. This oil was dissolved in anhydrous ethanol (5 ml), acidified with etheric hydrogen chloride and diluted with anhydrous ether (20 ml).

Pour off from ether residual oil and replace with more anhydrous ether (200 ml). The mixture was left at 0 ° C. to crystallize the oil to give the title compound (0.53 g). Melting point 144 ° C-147 ° C.

NMR δ (CD ₃ SOCD ₃ ): 0.09 and 0.93 (6H, t + t, 2 × Me), 1.65-2.2 and 2.9-3.25 (10H, m), 4.19 (H, t, CH ₂ CH ₂ N), 4.32 and 4.71 (2H, ABX, CH ₂ CH ₂ N), 7.15-8.1 (6H, m aromatic).

Elemental Analysis for C ₂₂ H ₂₇ N ₃ O · HCl · 0.7H ₂ O

Found: C; 66.6, H; 7.7, N; 10.0

Theoretical: C; 66.3, H; 7.4, N; 10.5%

Example 17

1,2,3,9-tetrahydro-3-[(2-methyl-1H-imidazol-1-yl) methyl] -9-propyl-4H-carbazol-4-one maleate

The solution of the product of Example 6 (0.86 g) in a mixture of anhydrous ethanol (20 ml) and anhydrous dimethylformamide (5 ml) was dried over 5% palladium on carbon [0.1 g, pre-depressurized in anhydrous ethanol (10 ml)] at room temperature. Hydrogenation was carried out under pressure for 1 hour (H ₂ absorption amount = 70 ml). The catalyst was filtered off, washed with ethanol and the filtrate was concentrated in vacuo to about 15 ml. The residual solution was stirred, diluted with water (50 ml), and the resulting precipitated solid was filtered, washed with water (3 × 15 ml) and dried to give a powder (0.73 g). The material was dissolved in reflux anhydrous ethanol (7 ml) and filtered, followed by addition of a maleic acid (0.25 g) solution in reflux anhydrous ethanol (1 ml). The stirred solution was diluted with anhydrous ether (50 ml) to afford the title compound (0.84 g). Melting point 150 ° C-151 ° C.

C ₂₀ H ₂₃ N ₃ OC ₄ H ₄ O ₄

Found: C; 65.8, H; 6.1, N; 9.3

Theoretical: C; 65.9, H; 6.2, N; 9.6%

Example 18

1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one

i) 3- (chloromethyl) -1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one

The ethereal hydrogen chloride (3.0) was cooled to ice water temperature and added to a solution of the product of Preparation 3 (1.90 g) in stirred chloroform (15 ml), and the resulting suspension was stirred for 16.5 hours at room temperature in a sealed container, followed by vacuum Concentrated, and the remaining solid (2.27g) was purified by column chromatography using chloroform as eluent to give the title compound (1.75g).

Melting point 109-110.5 ° C.

Attempts to crystallize some of the material with ethyl acetate resulted in partial decomposition.

ii) 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one

3- (chloromethyl) -1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one (0.50 g) and 2-methyl-1H-imidazole (1.60 g) in anhydrous DMF The solution of was stirred for 3.75 hours at 90 ° C. under nitrogen atmosphere, and then poured into water (25 ml). The suspension was stirred for 1 hour, filtered to give a solid, then washed with water (3 x 20 ml) and dried in vacuo at 50 ° C. The title compound (0.45 g) was obtained by column chromatography using a mixture of dichloromethane, ethanol and 0.88 aqueous ammonia solution (150: 10: 1) as eluent. Melting point 228-229 ° C.

The product was confirmed to be the same as the product of Example 7 by thin layer chromatography and NMR.

Example 19

1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one

A solution of 2,3-dichloro-5,6dicyano-1,4-benzoquinone (170 mg) in anhydrous tetrahydrofuran (1.5 ml) was cooled to ice water temperature under nitrogen atmosphere and stirred with tetrahydrofuran (3.5 ml) To the suspension of the product of Preparation 4 (100 mg) in a mixture of water (0.4 ml) and dropwise. The resulting blue solution was stirred for 1.5 hours and then concentrated in vacuo. The residue was subjected to column chromatography using a mixture of dichloromethane, ethanol and a 0.88 aqueous ammonia solution (150: 10: 1) as eluent to give the title compound (45 mg). Melting point 227 ° C-228.5 ° C. The material was identified to be the same as the product of Example 7 by thin layer chromatography and NMR.

Example 20

1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one

A solution of 2,3-dichloro-5,6-dicyano-1,4 benzoquinone (80 mg) in anhydrous tetrahydrofuran (1.5 ml) in a mixture of tetrahydrofuran (3.5 ml) and water (0.4 ml) under nitrogen atmosphere The product (100 g) of Preparation Example 5 was added dropwise to the suspension cooled to stirring and ice cooling temperature. After stirring the resulting blue solution for 1.5 hours, the red suspension was concentrated in vacuo.

The residue solid was subjected to column chromatography using a mixture of dichloromethane, ethanol and 0.88 ammonia (150: 10: 1) as eluent to obtain a white solid (0.47 g) of the title compound. Melting point 227.5 ° C-229 ° C.

This material was confirmed to be the same as the product of Example 7 by thin layer chromatography and NMR.

Example 21

3S-1,2,3,9-tetrahydro-3-[(2-methylimidazol-1-yl) methyl] -9-methyl-4H-carbazol-4-one maleate

The product of Example 7 (0.5 g) was dissolved in hot methanol (3 ml) and this was a hot solution of (+)-di-p-toluoyl-D-tartaric acid monohydrate (0.7%) in methanol (10 ml). After treatment, the resulting solution was crystallized overnight to give the desired salt (0.68 g). This salt was dissolved in hot dimethylformamide (DMF, 20 ml), diluted with hot water (10 ml) and crystallized overnight. The product was filtered off and dried in vacuo to afford (+)-di-p-toluoyl-D-tartarate (0.23 g) which was pure (represented by NMR) as about 90% enantiomer. Melting Point 231-233 ° C

A sample of salt (0.15 g) was partitioned between 8% sodium bicarbonate (25 ml) and chloroform (2 x 25 ml). The combined extracts were dried and then evaporated in vacuo to give pure free base (0.07 g). The base was dissolved in methanol (5 ml) acidified with maleic acid (0.03 g) and excess anhydrous ether (80 ml) was added to precipitate a salt to afford the title compound (0.062 g). Melting point 142-145 ° C.

-14℃(c 19 MeOH)를 나타내었다.Thin layer chromatography, silpica, dichloromethane / ethanol / 0.88 ammonia (100: 8: 1) Rf 0.3 Confirmed the same as the product in Example 7 by ultraviolet detection and iodine platinum acid method. The ethanethiomer ratio measured by ¹ H NMR was 93: 7 (S: R). Samples of maleate did not show marked optical rotation in methanol. The free base produced in maleate

-14 ° C (c 19 MeOH).

Example 22

3R-1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one maleate

The solution of Example 7 (0.5 g) was dissolved in hot methanol (30 ml) and a hot solution of (-)-di-p-toluoyl-L-tartaric acid monohydrate (0.7 g) in methanol (10 ml) After treatment, the resulting solution was crystallized overnight to give the desired salt (0.8 g). This salt was dissolved in hot dimethylformamide (DMF, 20 ml) and allowed to crystallize for 3 days after dilution with hot water (10 ml). The product was obtained by filtration and vacuumed to give (-)-di-P-toluoyl-L-tartarate (0.26 g) which was pure (represented by NMR) as about 95% enantiomer. Melting point 170 ° C-172 ° C.

A sample of this salt (0.2 g) was partitioned between 8% sodium bicarbonate (25 ml) and chloroform (2 x 25 ml). The mixed extract was dried and evaporated in vacuo to give pure free base (0.12 g). This base was dissolved in methanol (5 ml) acidified with maleic acid (0.045 g) and excess anhydrous ether (80 ml) was added to precipitate the salt to afford the title compound (0.08 g). Melting point 142 ° C-145 ° C.

+16℃(c 0.34, MeOH)를 나타내었다.Thin layer chromatography, silica, dichloromethane / ethanol / 0.88 ammonia (100: 8: 1) Rf 0.3 The same as the product of Example 7 was confirmed by ultraviolet detection and iodine platinum acid method. The enantiomer ratio measured by ¹ H NMR was> 95: 5. Samples of maleate did not show marked light rotation in methanol. The free base produced from maleic acid salt

+ 16 ° C. (c 0.34, MeOH).

The following example shows 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-amidazol-1-yl) methyl] -4H-carbazole-4- as an active ingredient. To describe a pharmaceutical composition according to the invention containing warm hydrochloride dihydrate (1.25 g of hydrochloride dihydrate contains 1.00 g of free base). Other compounds of the present invention can also be formulated in the same manner.

Tablets for oral administration

Tablets may be prepared by conventional methods such as direct compression or wet granulation.

Tablets may be film coated with a suitable film former such as hydroxypropyl methylcellulose using standard methods. Alternatively tablets may be sugar coated.

Direct crimp

* Suitable for direct crimping

The active ingredient was passed through a 60 mesh sieve and mixed with calcium hydrogenphosphate, croscarmellose sodium and magnesium stearate. The resulting mixture was compressed into tablets using a Manesty F3 tablet equipped with a 5.5 mm horizontal bevel edge punch.

The active ingredient is sieved through a suitable sieve, mixed with excipients and compressed using a suitable punch. Tablets of other concentrations may be made using an effective ingredient ratio or compression weight change for excipients and suitable punches.

Wet particles

The active ingredient is sieved with a suitable sieve and mixed with lactose, starch and pregelatinized corn starch. After the appropriate volume of washing water was added, the powder was made into particles. After drying, the particles were filtered off and mixed with magnesium stearate. The particles were compressed into tablets using a 7 mm diameter punch.

Different concentrations of tablets can be made by changing the effective ingredient ratio or compression weight for lactose and using a suitable punch.

The active ingredient was sieved through a suitable sieve and mixed with mannitol and hydroxypropylmethylcellulose. Appropriate volume of purified water was added and the powder was made into particles. After drying, the particles were filtered and formulated into tablets using a suitable punch.

Tablets of other concentrations may be formulated using a suitable punch by varying the active ingredient ratio or compression weight for mannitol.

* Starch form

The active ingredient is sieved and mixed with excipients. The mixture was filled into No. 2 hard gelatin capsules using a suitable device. Other dosage units can be prepared by varying the fill weight or, if necessary, into the appropriate capsule size.

Syrup

This formulation may be made in the form of sucrose-containing or sucrose-free.

The active ingredients, buffers, flavors, pigments and preservatives were dissolved in a small amount of water and glycerin was added. The residual water was heated until sucrose dissolved and then cooled. The two solutions were mixed and adjusted after adjusting the volume. The syrup was filtered and clarified.

Hydroxypropylmethylcellulose was dispersed in hot water and mixed with an aqueous solution containing the active ingredient and other compositional components after cooling. The resulting solution was mixed after adjusting to the proper volume. This syrup was filtered and clarified.

Injection

Injectables can be administered by the intravascular or subcutaneous route.

The active ingredient is dissolved in a suitable volume of sodium chloride injection solution (UK Pharmacopoeia), the pH of the resulting solution is adjusted to pH 3.5 with dilute hydrochloric acid (UK Pharmacopoeia), and the resulting solution is sodium chloride injection solution (UK Pharmacopoeia). ) And mix well by volume. The solution was filled into a 5 ml ampoule of Type 1 clear glass, sealed by air sealing under air in a constant head space, and autoclaved at 120 ° C. for at least 15 minutes to sterilize.

Instrumentation Dose Pressurized Aerosol

The active ingredient was refined to particulate size using a fluid energy mill. Oleic acid was mixed with trichloro pullulo methane at 10-15 ° C. and the particulated drug was mixed with the solution in a high shear mixer. The suspension was filled into an aluminum aerosol can while the suspension was measured, and a suitable metering valve for dispensing 85 mg of the suspension was crimped into the can and pressurized to the can via a dichlorodifluoromethanol valve.

Oleic acid BF or a suitable surfactant (eg, may also include Span 85 (trioleic acid sorbitan))

When oleic acid or a surfactant was used, the active ingredient was dissolved in ethanol together with them. The alcohol solution was totally transferred to a suitable aerosol container while metering, followed by trichlorofluoromethane. A suitable metering valve was crimped into the vessel and pressure charged with dichloro difluoromethane through the valve.

Prior to mixing the active ingredient with tabletting grade lactose, which is common in high energy mixers, it is refined to particulate size in a fluid energy mill. The powder mixture was filled into No. 3 hard gelatin capsules using a suitable encapsulation substrate. The contents of the cartridge are fed using a powder inhaler.

Claims (23)

The compound of formula (II) or a protective derivative thereof is reacted with an imidazole of formula (III) or a salt thereof to obtain a compound of formula (I), wherein the compound of formula (I) is enantio When obtained as a mixture of mers, the mixture is optically divided to obtain the desired enantiomer, or when the compound of formula (I) is a free base, the free base is converted to a salt. A process for producing a compound of formula (I), or a physiologically acceptable salt or solvent compound thereof.

In each of the above formula, R ¹ is a hydrogen atom or C _1-10 alkyl, C _3-7 cycloalkyl, C _3-6 alkenyl, phenyl or phenyl-C _1-3 alkyl, R ² , R ³ and R ⁴ One of the groups represented by is a hydrogen atom or a C _1-6 alkyl, C _3-7 cycloalkyl, C _2-6 alkenyl or phenyl-C _1-3 alkyl group, and the other two groups are the same or different from each other, A hydrogen atom or a C _1-6 alkyl group, and Y is a reactive substituent. The method of claim 1, wherein R ¹ is a hydrogen atom or a C _1-6 alkyl, C _3-6 cycloalkyl or C _3-6 alkenyl group. The compound of claim 1 or 2, wherein one of R ² , R ³ and R ⁴ is a C _1-3 alkyl, C _3-6 cycloalkyl or C _3-6 alkenyl group, and the other two groups are the same as each other or Different, each being a hydrogen atom or a C _1-3 alkyl group. 2. A compound according to claim 1, wherein R ¹ is a hydrogen atom or a C _1-6 alkyl, C _5-6 cycloalkyl or C _3-4 alkenyl group, R ² is a hydrogen atom, R ³ and (or) R ⁴ is Or a C _1-3 alkyl group or R ² is a C _1-3 alkyl group and both R ³ and R ⁴ groups are hydrogen atoms. The process according to claim 1, wherein the compound of formula (Ia) or a physiologically acceptable salt or solvent compound thereof is prepared.

Wherein R ¹ a is a hydrogen atom or methyl, ethyl, propyl, prop-2-yl, prop-2-enyl or cyclopentyl group, R ³ a is a hydrogen atom, R ² a is methyl, An ethyl, propyl or prop-2-yl group, R ⁴ a is a hydrogen atom, or R ² a is a hydrogen atom, and R ⁴ a is a methyl or ethyl group. The compound of claim 1, wherein 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one or Process for the preparation of physiologically acceptable salts or solvent compounds thereof. The compound of claim 1, wherein the 1,2,3,9-tetrahydro-3-[(2-methyl-1H-imidazol-1-yl) methyl] -9- (prop-2-enyl) -4H- Carbazol-4-one, 9-cyclopentyl-1,2,3,9-tetrahydro-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazole-4- On, 1,2,3,9-tetrahydro-3-[(2-methyl-1H-imidazol-1-yl) methyl] -9- (prop-2-yl) -4H-carbazole-4 -One, or a method for preparing a physiologically acceptable salt or solvent compound thereof. The method of claim 1, wherein Y is a = CH ₂ group or a CH ₂ Z group, where Z is an easily substituted atom or group. The hydrochloride salt according to claim 6, wherein the 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one hydrochloride Method of preparation. The hydrochloride salt according to claim 6, wherein the 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one hydrochloride Method for preparing dihydrate. The compound of formula (IV), or a salt or protective derivative thereof, is oxidized to obtain a compound of formula (I), which is a mixture when the compound of formula (I) is obtained as a mixture of enantiomers. Optically dividing to obtain the desired enantiomer, or when the compound of formula (I) is a free base, the compound of formula (I) Or a process for preparing a physiologically acceptable salt or solvent compound thereof.

In each formula, R_OneIs a hydrogen atom, or C_1-10Alkyl, C_3-7Cycloalkyl, C_3-6Alkenyl, phenyl or phenyl-C_1-3Alkyl group, R², R³And R⁴One of the groups represented by is a hydrogen atom, or C_1-6Alkyl, C_3-7Cycloalkyl, C_2-6Alkenyl or phenyl-C_1-3Alkyl group, and the other two groups are the same or different from each other, and each hydrogen atom, or C_1-6An alkyl group, and A is a hydrogen atom or a hydroxyl group. 12. The compound of claim 11, wherein 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one or Process for the preparation of physiologically acceptable salts or solvent compounds thereof. 13.Hydrochloric acid according to claim 12, wherein the 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one hydrochloride Method of preparation. 13.Hydrochloric acid according to claim 12, wherein the 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one hydrochloride Method for preparing dihydrate. The compound of formula (I), or a salt or protective derivative thereof, is converted to another compound of formula (I), and when the converted compound of formula (I) is obtained as a mixture of enantiomers, The mixture is optically partitioned to give the desired enantiomer, or when the compound of formula (I) is a free base, this free base is converted to a salt, the compound of formula (I) Or a process for preparing a physiologically acceptable salt or solvent compound thereof.

Wherein R ¹ is a hydrogen atom or C _1-10 alkyl, C _3-7 cycloalkyl, C _3-6 alkenyl, phenyl or phenyl-C _1-3 alkyl group, represented by R ² , R ³ and R ⁴ One of the groups is a hydrogen atom or a C _1-6 alkyl, C _3-7 cycloalkyl, C _2-6 alkenyl or phenyl-C _1-3 alkyl group, the other two groups being the same or different from each other, each hydrogen atom Or a C _1-6 alkyl group. The method of claim 15, wherein the compound of formula (I), or a salt or protecting derivative thereof, is converted to another compound of formula (I) by alkylation or hydrogenation. The method of claim 15 or 16, wherein 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazole- A method of preparing a 4-one or physiologically acceptable salt or solvent compound thereof. 18. The composition of claim 17 of 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one hydrochloride Manufacturing method. 18. The compound of claim 17, wherein 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one hydrochloride Method for preparing dihydrate. The protecting groups are removed from the protected form of the compound of the general formula (I) to obtain the compound of the general formula (I), which is the compound if the compound of the general formula (I) is obtained as a mixture of enantiomers Optically dividing to obtain the desired enantiomer, or when the compound of formula (I) is a free base, this free base is converted to a salt, or a compound of formula (I) Process for the preparation of physiologically acceptable salts or solvent compounds thereof.

Wherein R ¹ is a hydrogen atom or a C _1-10 , alkyl, C _3-7 cycloalkyl, C _3-6 alkenyl, phenyl or phenyl-C _1-3 alkyl group, R ² , R ³ and R ⁴ One of the groups represented by is a hydrogen atom or a C _1-6 alkyl, C _3-7 cycloalkyl, C _2-6 alkenyl or phenyl-C _1-3 alkyl group, the other two being the same or different from each other, It is a hydrogen atom or a C _1-6 alkyl group. The compound of claim 20, wherein 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one or Process for the preparation of physiologically acceptable salts or solvent compounds thereof. The hydrochloride salt of claim 21, wherein the 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one hydrochloride Method of preparation. The hydrochloride salt of claim 21, wherein the 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one hydrochloride Method for preparing dihydrate.